On the role of prolyl oligopeptidase in health and disease

Abstract 

Prolyl oligopeptidase (POP) is a serine peptidase which digests small peptide-like hormones, neuroactive peptides, and various cellular factors. Therefore, this peptidase has been implicated in many physiological processes as well as in some psychiatric disorders, most probably through interference in inositol cycle. Intense research has been performed to elucidate, on the one hand, the basic structure, ligand binding, and kinetic properties of POP, and on the other, the pharmacology of its inhibitors. There is fairly strong evidence of in vivo importance of POP on substance P, arginine vasopressin, thyroliberin and gonadoliberin metabolism. However, information about the biological relevance of POP is not yet conclusive. Evidence regarding the physiological role of POP is lacking, which is surprising considering that peptidase inhibitors have been exploited for drug development, some of which are currently in clinical trials as memory enhancers for the aged and in a variety of neurological disorders. Here we review the recent progress on POP research and evaluate the relevance of the peptidase in the metabolism of various neuropeptides. The recognition of novel forms and relatives of POP may improve our understanding of how this family of proteins functions in normal and in neuropathological conditions.

Keywords: Prolyl oligopeptidase, Neuropeptide metabolism, Memory and learning, Inositol cycle, Substance P, Arginine-vasopressin, Thyroliberin, Gonadoliberin

Abbreviations: ACD, active coeliac disease, ACE, angiotensin-coverting enzyme, ACPH, acylaminoacyl peptidase, AD, Alzheimer’s disease, AEBSF, 4-(2-aminoethyl)benzenesulfonyl fluoride, Agt, angiotensinogen, AMC, 7-Amino-4-methylcoumarin, Ang, angiotensins, AVP, arginine-vasopressin, BK, bradykinin, CD, coeliac disease, CSF, cerebrospinal fluid, DPPIV, dipeptidyl peptidase IV, DTT, dithiothreitol, FAP, fibroblast activation protein, GAPDH, glyceraldehyde-3-phosphate dehydrogenase, GnRH, gonadotropin releasing hormone, GSSG, the oxidized glutathione form, HD, Huntington disease, IMPase, inositol monophosphatase, Ins(1,4,5)P3, or IP3, inositol 1,4,5-triphosphate, IPPase, inositol polyphosphate 1-phosphatase, LH, luteinizing hormone, MInsPP, multiple inositol polyphosphate polyphosphatase, MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, NEP, neutral endopeptidase, NK1, neurokinin-1, NK3, neurokinin-3, OB, oligopeptidase B, PAP I, pyroglutamyl aminopeptidase I, PAP II, pyroglutamyl aminopeptidase II, PD, Parkinson’s disease, PEP, prolyl endopeptidase, PLC, phospholipase C α, PMSF, phenylmethylsulfonyl fluoride, POP, prolyl oligopeptidase, PPCE, post-proline cleaving enzyme, RAS, renin-angiotensin system, SP, substance P, SPLI, substance P-like immunoreactivity, TCD, treated coeliac disease, TRF, thyrotropin releasing factor, TRH, thyrotropin releasing hormone, TRH-LI, thyrotropin releasing hormone-like immunoreactivity, VPA, valproic acid, ZIP, ZPP insensitive POP, ZPP, benzyloxycarbonyl-Pro-Prolinal, ZTTA, N-benzyl-oxycarbonyl-thioprolyl-thioprolynal-dimethylacetal, α-MSH, α-Melanocyte-stimulating hormone, β-E, β-endorphin